title: Effect of CYP2C19 polymorphism on the pharmacokinetics of voriconazole after single and multiple doses in healthy volunteers.
abstract: The current study assessed the influence of the CYP2C19 genotype on the pharmacokinetics and tolerability of voriconazole after single and multiple oral doses in healthy volunteers. Six subjects for the CYP2C19 homozygous extensive metabolizer (EMs), 6 for heterozygous extensive metabolizer (HEMs), and 6 for poor metabolizer (PMs) were enrolled, and their CYP2C9, CYP3A5, and MDR1 genotypes were analyzed. After a single intravenous infusion or single and multiple oral doses of 200 mg of voriconazole, plasma concentrations of voriconazole were measured. Bioavailability was not significantly different among the CYP2C19 genotypes. Voriconazole exposure in PMs was approximately 3 times higher compared with EMs after a single intravenous or oral dose. At steady state, the plasma concentration just before the next dosing and area under the concentration-time curve from dosing to the time point of the next dosing for PMs were about 5 times and 3 times higher than EMs, respectively. These results suggest that the CYP2C19 genotype is the major determinant of the wide PK variability of voriconazole.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: SeungHwan
authors.initials: S
authors.lastname: Lee
authors.forename: Bo-Hyung
authors.initials: BH
authors.lastname: Kim
authors.forename: Won-Seok
authors.initials: WS
authors.lastname: Nam
authors.forename: Seo Hyun
authors.initials: SH
authors.lastname: Yoon
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000935:Antifungal Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D065819:Voriconazole / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000935:Antifungal Agents; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065819:Voriconazole